The islets of Langerhans are multi-cellular micro-organs central to regulating blood glucose through the secretion of insulin and glucagon. Diabetes, a world-wide epidemic affecting ~400M people, ultimately arises due to a dysfunction of insulin-secreting -cells in the islet. Most genetic mutations that cause diabetes or elevate te risk of diabetes are associated with disrupting insulin secretion. While signaling within the -cel that regulates insulin is fairly well understood - consisting of a series of metabolic, electrical nd other cell signaling events - -cells do not act autonomously. Rather complex, dynamic cellular interactions are required to tightly regulate both the dynamic range and the pulsatile dynamics of insulin release, and these can be disrupted in diabetes. We have discovered how electrical coupling mediated by gap junction channels plays a key role to coordinate the dynamic electrical response underlying insulin release. However a key question is how properties of the individual -cells impact the islet-wide response upon coupling. This is important for several reasons: individual -cells are highly heterogeneous in terms of their signaling dynamics and response to glucose; mutations that cause diabetes shift the population-level response non-uniformly, and sub-populations of cells that show differing function are present in development and through many pathogenic conditions associated with diabetes. Therefore, towards our goal of understanding how properties of the -cell population impact the islet-level response when coupled, our overall hypothesis is: small changes in the regulation of electrical activity within te heterogeneous cellular population tightly control overall islet function upon electrical coupling. We will test this through 3 specific aims that combine quantitative experimental measurements and predictive mathematical models of multicellular islet signaling: 1) how coupling suppresses global activity under inhibitory conditions (such as upon diabetes-causing mutations), and the importance for the distribution in excitability of the -cell population; 2) how coupling coordinaes global dynamics under excitatory conditions, and how sub-populations of -cells exert control of the overall dynamics; and 3) how interactions between [Ca2+] and cAMP signaling can promote their coordination between -cells. Through understanding the population-level regulation and interactions within the islet, we will discover novel ways the global response of the islet can be controlled and how it may be disrupted in diabetes. This can be applied to overcome genetic mutations or other conditions of islet dysfunction that cause diabetes. Further, we anticipate many principles governing islet function will be broadly relevant to further our understanding of the emergent multicellular properties of physiological systems.